Systemic lupus erythematosus (SLE) is a disease characterized by multiple immunological abnormalities. Peripheral blood mononuclear cells from SLE patients exhibit reduced spontaneous and antibody dependent cytotoxicity (ADCC) against tumor cell targets. The effector cells which are functionally defined as natural killer (NK) and killer (K) cells, form a discrete leukocyte subpopulation and constitute 5-15% of normal circulating mononuclear cells. Although their role in the human immune system has not been completely defined, they are able to kill tumor, virus infected and normal tissue cells sensitized with antibody or not. Reduced cell mediated cytotoxicity in humans with SLE could be due to a decreased number of effector cells or suppression by cellular or humoral modulation. However it could actually be due to a continuous and chronic activation of the NK/K cells (by immune complex, IFN) that exhausts their cytotoxic activity or leads to their sequestration outside the circulation. The many different types of cells coated with antibody in SLE patients are potential targets for K cell cytotoxicity. If the NK/K cells are chronically activated and killing these antibody coated cells in vivo, then they may be responsible for several of the clinical and pathological manifestations of SLE in humans and a more profound understanding of this process may provide a rationale for future therapeutic strategy. The central objective of this proposal will therefore be to define the role and functional state of the NK/K cell subset in human SLE. This will be accomplished by: 1) quantifying these cells in the peripheral blood with an anti-NK monoclonal antibody, B73.1; 2) studying spontaneous cytotoxicity and ADCC accounting for potential modulating factors; 3) examining for clues of NK/K cell activation, such as HLA-DR antigen, IL-2 receptors, adherent properties, and others on B73.1(+) cells and 4) studying pathological SLE biopsy specimens for evidence of NK/K cell presence by indirect immunofluorescent staining with monoclonal antibodies.